title: Elite suppressors harbor low levels of integrated HIV DNA and high levels of 2-LTR circular HIV DNA compared to HIV+ patients on and off HAART.
abstract: Elite suppressors (ES) are a rare population of HIV-infected individuals that are capable of naturally controlling the infection without the use of highly active anti-retroviral therapy (HAART). Patients on HAART often achieve viral control to similar (undetectable) levels. Accurate and sensitive methods to measure viral burden are needed to elucidate important differences between these two patient populations in order to better understand their mechanisms of control. Viral burden quantification in ES patients has been limited to measurements of total DNA in PBMC, and estimates of Infectious Units per Million cells (IUPM). There appears to be no significant difference in the level of total HIV DNA between cells from ES patients and patients on HAART. However, recovering infectious virus from ES patient samples is much more difficult, suggesting their reservoir size should be much smaller than that in patients on HAART. Here we find that there is a significant difference in the level of integrated HIV DNA in ES patients compared to patients on HAART, providing an explanation for the previous results. When comparing the level of total to integrated HIV DNA in these samples we find ES patients have large excesses of unintegrated HIV DNA. To determine the composition of unintegrated HIV DNA in these samples, we measured circular 2-LTR HIV DNA forms and found ES patients frequently have high levels of 2-LTR circles in PBMC. We further show that these high levels of 2-LTR circles are not the result of inefficient integration in ES cells, since HIV integrates with similar efficiency in ES and normal donor cells. Our findings suggest that measuring integration provides a better surrogate of viral burden than total HIV DNA in ES patients. Moreover, they add significantly to our understanding of the mechanisms that allow viral control and reservoir maintenance in this unique patient population.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Erin H
authors.initials: EH
authors.lastname: Graf
authors.forename: Angela M
authors.initials: AM
authors.lastname: Mexas
authors.forename: Jianqing J
authors.initials: JJ
authors.lastname: Yu
authors.forename: Farida
authors.initials: F
authors.lastname: Shaheen
authors.forename: Megan K
authors.initials: MK
authors.lastname: Liszewski
authors.forename: Michele
authors.initials: M
authors.lastname: Di Mascio
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Migueles
authors.forename: Mark
authors.initials: M
authors.lastname: Connors
authors.forename: Una
authors.initials: U
authors.lastname: O'Doherty
mesh_terms: D023241:Antiretroviral Therapy, Highly Active; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D015331:Cohort Studies; D004270:DNA, Circular / Q000235:genetics*; D004279:DNA, Viral / Q000235:genetics*; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D016325:HIV Long Terminal Repeat / Q000235:genetics; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D019562:Viral Load; D016662:Virus Integration
chemical_list: D004270:DNA, Circular; D004279:DNA, Viral